Current Research and Scholarly Interests

Clinical Trials

You are invited to participate in a research study assessing your mental status in the first
days after your surgery and how you will be doing in the 2 years following the surgery. The
investigators hope to learn more about the incidence of postoperative confusion and a
possible relation with 2 anesthesia techniques that are routinely used. The first one is an
anesthesia technique that uses the inhaled anesthetic gas desflurane and the second one is an
anesthesia technique that uses the anesthetic propofol administered by infusion in a vein.
The investigators are also looking to see if there is a relationship between anesthesia
technique and cardiovascular outcomes. You were selected as a possible participant in this
study because at your age this phenomenon appears to have a greater incidence.

Abstract

The use of flexible laryngeal mask airway (FLMA) in elective ear, nose and throat (ENT) surgery offers significant advantages, but is frequently considered inferior to tracheal intubation (TI) for ventilation and airway protection. We investigated the safety and success rate of intraoperative FLMA use with positive pressure ventilation (PPV), and the factors responsible for FLMA failure.A 15-year single center retrospective study. FLMA failure was defined as the need for FLMA removal and TI, either during induction (primary failure), or after turning the patient over to the surgeon (secondary failure). Strict failure criteria included the inability to achieve and/or maintain all 3 essential FLMA functions, such as ventilation (tidal volume ≥ 6 ml/kg), airway protection from above the cuff (airway sealing pressure, (ASP) > 12 cm H2O), and separation of the respiratory and gastrointestinal tracts (absent gastric insufflation during PPV).In 685 patients, FLMA was successfully inserted in 94%. Secondary failure rate was 1.5%, with half of failures observed intraoperatively. The inability to seat FLMA during induction or FLMA dislodgment were the most common reasons for failures. The number of FLMA insertion attempts and low ASP were associated with FLMA primary failure and the need for TI. There were no complications.The results suggest an acceptably low failure rate of use of FLMA with PPV in selected ENT surgical procedures. True intraoperative FLMA failure is uncommon. We advocate observing strict criteria for adequacy of FLMA placement, and close monitoring of FLMA function intraoperatively at all times.

Abstract

Anesthesiologists are unique among most physicians in that they routinely use technology and medical devices to carry out their daily activities. Recently, there have been significant advances in medical technology. These advances have increased the number and utility of medical devices available to the anesthesiologist. There is little doubt that these new tools have improved the practice of anesthesia. Monitoring has become more comprehensive and less invasive, airway management has become easier, and placement of central venous catheters and regional nerve blockade has become faster and safer. This review focuses on key medical devices such as cardiovascular monitors, airway equipment, neuromonitoring tools, ultrasound, and target controlled drug delivery software and hardware. This review demonstrates how advances in these areas have improved the safety and efficacy of anesthesia and facilitate its administration. When applicable, indications and contraindications to the use of these novel devices will be explored as well as the controversies surrounding their use.

Abstract

The development of fundamental pharmacokinetics and pharmacodynamics concepts has enabled anesthesiologists to choose and dose anesthetic agents on a rational basis. The application of these concepts to a variety of clinical scenarios and patient populations makes it possible to individualize the dose, thereby decreasing the risk of complications. As more knowledge is gained about the sometimes profound differences in drug response, empirical dosing such as in milligrams per kilogram of total body weight is disappearing from the anesthesia specialty.

Abstract

The unique anesthetic risks associated with the morbidly obese (MO) population have been documented. Pharmacologic management of these patients may be altered because of the physiologic and anthropometric changes associated with obesity. Unfortunately, studies examining the effects of extreme obesity on the pharmacology of anesthetics have been sparse. Although propofol is the induction drug most frequently used in these patients, the appropriate induction dosing scalar for propofol remains controversial in MO subjects. Therefore, we compared different weight-based scalars for dosing propofol for anesthetic induction in MO subjects.Sixty MO subjects (body mass index ≥40 kg/m(2)) were randomized to receive a propofol infusion (100 mg · kg(-1) · h(-1)) for induction of anesthesia based on total body weight (TBW) or lean body weight (LBW). Thirty control subjects (body mass index ≤25 kg/m(2)) received a propofol infusion (100 mg · kg(-1) · h(-1)) based on TBW. Syringe drop was used as the marker for loss of consciousness (LOC), at which point the propofol infusion was stopped. The propofol dose required for syringe drop and time to LOC were recorded.Total propofol dose (mg/kg) required for syringe drop and time to LOC were similar between control subjects and MO subjects given propofol based on LBW. MO subjects receiving a propofol infusion based on TBW had a significantly larger propofol dose and significantly shorter time to LOC. There was a strong relationship between LBW and total propofol dose received in all 3 groups.LBW is a more appropriate weight-based scalar for propofol infusion for induction of general anesthesia in MO subjects.

Abstract

Anaesthesiologists must be prepared to deal with pharmacokinetic and pharmacodynamic (PD) differences in morbidly obese individuals. As drug administration based on total body weight can result in overdose, weight-based dosing scalars must be considered. Conversely, administration of drugs based on ideal body weight can result in a sub-therapeutic dose. Changes in cardiac output and alterations in body composition affect the distribution of numerous anaesthetic drugs. With the exception of neuromuscular antagonists, lean body weight is the optimal dosing scalar for most drugs used in anaesthesia including opioids and anaesthetic induction agents. The increased incidence of obstructive sleep apnoea and fat deposition in the pharynx and chest wall places the morbidly obese at increased risk for adverse respiratory events secondary to anaesthetic agents, thus altering the PD properties of these drugs. Awareness of the pharmacology of the commonly used anaesthetic agents including induction agents, opioids, inhalation agents and neuromuscular blockers is necessary for safe and effective care of morbidly obese patients.

Abstract

This study was undertaken to compare the effect of deep hypothermic circulatory arrest, compared with moderate hypothermia, on the plasma concentrations and pharmacokinetic profile of vancomycin, administered as prophylaxis, in patients undergoing cardiac surgery with cardiopulmonary bypass.Two groups of adult cardiac surgery patients were prospectively studied. One group consisted of 12 patients undergoing valvular surgery with moderate hypothermia, and another group was of 12 patients undergoing surgery with the use of profound hypothermic circulatory arrest. Vancomycin was administered before skin incision, and plasma levels were measured at regular intervals for 24h.The plasma concentrations of vancomycin showed a similar pattern in both groups. The pharmacokinetic profile showed a three-compartment model in both groups.The dosing of vancomycin, if used as antibiotic prophylaxis, does not need to be adjusted in cardiac surgery patients when undergoing profound hypothermic circulatory arrest, since the plasma concentrations and pharmacokinetic profile are similar to patients with moderate hypothermia. The pharmacokinetic profile, consisting of three compartments, was not changed by the differences in temperature.

Abstract

Transcranial electrostimulation (TES) has been reported to produce clinically significant analgesia, but randomized and double-blind studies are lacking. We investigated the analgesic and antihyperalgesic effects of TES in validated human experimental pain models.In 20 healthy male subjects we evaluated the analgesic and antihyperalgesic effects of TES(60Hz) and TES(100Hz) to heat and mechanical pain in experimentally induced ultraviolet B skin sunburns and in normal skin. Previous animal studies in our laboratory predicted that TES(60Hz) would provide significant analgesia, and TES(100Hz) was a suitable active control. The study was conducted in a double-blind, randomized, 2-way cross-over fashion. TES was administered for 35 minutes. Quantitative sensory testing evaluating heat and mechanical pain thresholds was conducted before TES, during TES, and 45 minutes after TES.TES (TES(60Hz) > TES(100Hz)) evoked rapidly developing, significant thermal and mechanical antihyperalgesic effects in the ultraviolet B lesion, and attenuated thermal pain in unimpaired skin. No long-lasting analgesic and antihyperalgesic effects of a single TES treatment were demonstrated in this study.TES produces significant, frequency-dependent antihyperalgesic and analgesic effects in humans. The characteristics of the TES effects indicate a high likelihood of its ability to modulate both peripheral sensitization of nociceptors and central hyperexcitability.

Abstract

Morbid obesity alters drug dose requirement and time course of drug response. In addition, morbid obesity's impact on many organ systems decreases the margin of safety of anesthetic drugs. Consequently, incorrect dosing will increase the rate of perioperative complications. In this review, we will discuss factors that affect the pharmacokinetics and pharmacodynamics of anesthetic agents in the obese population, we specify certain dosing scalars, and we relate our current knowledge of obesity's effects on the clinical pharmacology of anesthetic drugs.A morbidly obese individual's increased cardiac output requires administration of higher drug doses than would be required for a standard-size person to attain the same peak-plasma concentration. Lean body weight (LBW) is highly correlated with the increased cardiac output, more so than fat mass or other variables. For most drugs, clearance increases nonlinearly with total body weight but linearly with LBW. Morbid obesity has no clinically significant impact on the uptake of the inhalation anesthetics isoflurane, sevoflurane, and desflurane when used in routine clinical practice. Total body weight dosing of neuromuscular blocking agents will result in a prolonged effect.For the induction dose of hypnotics and the initial dose of other drugs that have a fast onset of effect, cardiac output or LBW are relevant dosing scalars. For maintenance dosing, LBW seems to be a more appropriate dosing scalar than total body weight.

Abstract

Morbid obesity and bariatric surgery are both risk factors for the development of postoperative rhabdomyolysis (RML). RML results from injury to skeletal muscle, and a serum creatine phosphokinase (CK) level >1,000 IU/L is considered diagnostic of RML. The aim of this study was to determine if intraoperative intravenous fluid (IVF) volume affects postoperative CK levels following laparoscopic bariatric operations.Prospective, single blinded, and randomized trial was conducted.Patients scheduled to undergo laparoscopic sleeve gastrectomy, adjustable gastric band, or Roux-en-Y gastric bypass operations were randomized into two groups. Subjects in Group A received 15 ml/kg total body weight (TBW) of IV crystalloid solution during surgery, while subjects in Group B received 40 ml/kg TBW. Preoperative and postoperative CK and creatinine levels and intra- and postoperative urine output were monitored and recorded.Forty-seven patients were assigned to Group A and 53 patients to Group B. Group B patients had significantly higher urine output in the operating room, in the post-anesthesia care unit (PACU), and on postoperative days 0 and 1. Group B patients also had significantly lower serum creatinine level in the PACU and a trend towards lower creatinine levels on postoperative days 0, 1, and 2. There were no statistical differences in CK levels at any time between the two groups. Four patients in Group A and three patients in Group B developed postoperative RML.Conservative (15 ml/kg) versus liberal (40 ml/kg) intraoperative IVF administration did not change the incidence of RML in patients undergoing laparoscopic bariatric operations. Since the occurrence of RML in this patient population is relatively high, postoperative CK levels should be routinely obtained in patients at special risk.

Abstract

Worldwide, the number of overweight and obese patients has increased dramatically. As a result, anesthesiologists routinely encounter obese patients daily in their clinical practice. The use of regional anesthesia is becoming increasingly popular for these patients. When appropriate, a regional anesthetic offers advantages and should be considered in the anesthetic management plan of obese patients. The following is a review of regional anesthesia in obesity, with special consideration of the unique challenges presented to the anesthesiologist by the obese patient.Recent studies report difficulty in achieving peripheral and neuraxial blockade in obese patients. For example, there is an increased incidence of failed blocks in obese patients compared with similar, normal weight patients. Despite difficulties, regional anesthesia can be used successfully in obese patients, even in the ambulatory surgery setting.Successful peripheral and neuraxial blockade in obese patients requires an anesthesiologist experienced in regional techniques, and one with the knowledge of the physiologic and pharmacologic differences that are unique to the obese patient.

Abstract

Few studies have determined the effect of obesity on inhaled anesthetic pharmacokinetics. We hypothesized that the solubility of potent inhaled anesthetics in fat and increased body mass index (BMI) in obese patients interact to increase anesthetic uptake and decrease the rate at which the delivered (FD) and inspired (FI) concentrations of an inhaled anesthetic approach a constantly maintained alveolar concentration (end-tidal or FA). This hypothesis implies that the effect of obesity would be greater with a more soluble anesthetic such as isoflurane versus desflurane.In 107 ASA physical status I-III patients, anesthesia was induced with propofol, tracheal intubation facilitated with neuromuscular blockade, and ventilation controlled with 50% nitrous oxide in oxygen to maintain end-tidal carbon dioxide concentrations between 35 and 45 mm Hg. Isoflurane or desflurane was administered in a 1 L/min inflow rate at FD concentrations sufficient to maintain FA at 0.6 minimum alveolar anesthetic concentration (0.7% or 3.7%, respectively). FD, FI, and FA were measured 5, 10, 20, 40, 60, 90, 120,150, and 180 min after starting potent inhaled anesthetic delivery.Fifty-nine patients received isoflurane and 48 received desflurane. BMI ranged between 18 and 63 kg/m(2) and demographic variables did not differ between anesthetic groups. For isoflurane, FD/FA or FI/FA weakly (but significantly) correlated with BMI at 9/18 time points whereas for desflurane FD/FA or FI/FA correlated significantly with BMI at only one time point (P < 0.01). After dividing each group into nonobese (BMI < 30) and obese (BMI > or = 30) patients, with isoflurane, FD/FA or FI/FA was higher in obese patients at four time points whereas there was no difference between nonobese and obese patients for desflurane. Patients receiving isoflurane took longer to respond to command after discontinuing anesthesia but obesity did not increase or decrease awakening time for either isoflurane or desflurane. When BMI was used to normalize FI/FA and FD/FA the median values for isoflurane consistently exceeded the median value for desflurane by factors ranging from 3 to 5, values comparable to the ratios of their blood/gas (3.1), muscle/gas (4.6), and fat/gas (5.4) partition coefficients.BMI modestly affects FD/FA and FI/FA, and this effect is most apparent for an anesthetic having a greater solubility in all tissues. An increased BMI increases anesthetic uptake and, thus, the need for delivered anesthetic to sustain a constant alveolar anesthetic concentration, particularly with a more soluble anesthetic. However, the increase with an increased body mass is small.

Abstract

The placement of an internal jugular vein (IJV) catheter is considered to be more difficult in morbidly obese patients. The objective of this study was to compare the success of simulated IJV puncture between morbidly obese patients and a nonobese control group.Thirty-four morbidly obese patients with body mass index (BMI, kg/m(2)) >/=40 were compared with 36 patients with BMI < 30. Right IJV puncture was simulated using an ultrasound probe directed towards the sternal notch at the midpoint between the sternal notch and the mastoid process. The investigator placing the probe was blinded as to the image being created on the ultrasound machine. Success rate was assessed at three different head rotation angles from midline; 0 degrees , 30 degrees , and 60 degrees .There was no statistically significant difference in successful simulated IJV puncture between two groups for any of the head positions. However, there was a higher incidence of the carotid artery (CA) puncture in the morbidly obese patient group when the head rotation was advanced from neutral position to 60 degrees (p < 0.05). In addition, the ultrasound showed significantly more overlapping of the IJV over the CA in morbidly obese patients at 0 degrees (p < 0.05) and 30 degrees (p < 0.05). Our results show no statistically significant difference in success rate of IJV puncture between morbidly obese patients and nonobese patients. Keeping the head in a neutral position in morbidly obese patients minimizes the overlapping of the IJV over the CA and the risk of CA puncture.However, due to the fact that even in the neutral position there is a significant increase in overlap between IJV and CA, we recommend the use of ultrasound guidance for IJV cannulation in obese patients.

Abstract

Activating clotting time (ACT) is a point-of-care, blood clotting test used to monitor anticoagulation. Recently, institutional requirements have required that ACT testing be completed outside the operating room with trained, certified personnel other than anesthesia staff. For this reason, in this study, we looked at whether a delay in processing an ACT makes a significant difference to the ACT results. Twenty patients between 18 and 65 years of age consented to the study, each undergoing non-cardiac surgery, with no intraoperative administration of heparin. The study was approved by our Institutional Review Board. A blood sample was taken from the patient's arterial line in the operating room. Immediately afterward, 1 mL was placed into each of two ACT cartridges and the measurement was done in a Medtronic ACT2 machine. The first ACT value was 126.9 +/- 14.5 seconds. The ACT value at approximately 30 minutes was 108.3 +/- 20.3 seconds (p < .0001). The time between the first and last measurements was 29.4 +/- 3.0 minutes. The results suggest that the ACT values decrease over time between sampling all measurements. At approximately 30 minutes, the ACT values average 15% less than the control measurements. Therefore, it would seem prudent to determine ACT values immediately in the operating room without any delay, using point-of-care testing.

Abstract

Gas chromatography (GC) has often been considered the most accurate method to measure the concentration of inhaled anesthetic vapors. However, infrared (IR) gas analysis has become the clinically preferred monitoring technique because it provides continuous data, is less expensive and more practical, and is readily available. We examined the accuracy of a modern IR analyzer (M-CAiOV compact gas IR analyzer (General Electric, Helsinki, Finland) by comparing its performance with GC.To examine linearity, we analyzed 3 different concentrations of 3 different agents in O₂: 0.3, 0.7, and 1.2% isoflurane; 0.5, 1, and 2% sevoflurane; and 1, 3, and 6% desflurane. To examine the effect of carrier gas composition, we prepared mixtures of 1% isoflurane, 1 or 2% sevoflurane, or 6% desflurane in 100% O₂ (= O₂ group); 30%O₂+ 70%N₂O (= N₂O group), 28%O₂ + 66%N₂O + 5%CO₂ (= CO₂ group), or air. To examine consistency between analyzers, four different M-CAiOV analyzers were tested.The IR analyzer response in O2 is linear over the concentration range studied: IR isoflurane % = -0.0256 + (1.006 * GC %), R = 0.998; IR sevoflurane % = -0.008 + (0.946 * GC %), R = 0.993; and IR desflurane % = 0.256 + (0.919 * GC %), R = 0.998. The deviation from GC calculated as (100*(IR-GC)/GC), in %) ranged from -11 to 11% for the medium and higher concentrations, and from -20 to +20% for the lowest concentrations. No carrier gas effect could be detected. Individual modules differed in their accuracy (p = 0.004), with differences between analyzers mounting up to 12% of the medium and highest concentrations and up to 25% of the lowest agent concentrations.M-CAiOV compact gas IR analyzers are well compensated for carrier gas cross-sensitivity and are linear over the range of concentrations studied. IR and GC cannot be used interchangeably, because the deviations between GC and IR mount up to ± 20%, and because individual analyzers differ unpredictably in their performance.

Abstract

Anesthetic management during functional endoscopic sinus surgery is aimed at minimizing bleeding and establishing a near-perfect surgical field. We investigated whether deliberate intraoperative hypercapnia and hypocapnia may affect blood loss and quality of surgical field through a proposed modulating effect of different carbon dioxide (CO2) tension levels on nasal vasculature.One hundred and eighty patients were randomly assigned to normocapnia (end-tidal CO2 [ETco2] 37 +/- 2 mm Hg), hypercapnia (ETco2 60 +/- 2 mm Hg), and hypocapnia (ETco2 27 +/- 2 mm Hg) groups. Anesthetic management was with propofol and remifentanil infusions, nitrous oxide, and moderate controlled hypotension. Blood loss and operating conditions were assessed by the surgeon who was blinded to group assignment. Differences among the study groups, the effect of the study group and time on ETco2 levels and hemodynamic variables, and the association of blood loss with surgical covariates were analyzed.There were no differences in blood loss and quality of surgical field among the study groups. Patients in the hypocapnia group demonstrated the highest, and in the hypercapnia group, the lowest, requirements for remifentanil, labetalol, and administration of the antihypertensive medications in general. The computed tomography-graded severity of sinonasal disease and duration of surgery were the only independent predictors of intraoperative blood loss.CO2 management during functional endoscopic sinus surgery does not influence operating conditions or blood loss.

Abstract

Today, thoracic surgeons routinely perform complex operations on even the most complicated patient. However, just 75 years ago the ability to operate within the chest was strictly limited to only the simplest and quickest procedures. The dramatic advances in the specialty of thoracic surgery have closely paralleled the introduction of new anesthetic practices, equipment and drugs. This review will identify major events in the history of anesthesia for thoracic surgery.

Abstract

The potential advantages of regional anesthesia include minimal airway intervention, less cardiopulmonary depression, excellent postoperative analgesia, less postoperative nausea and vomiting, and shorter recovery room and hospital stays. These concerns are particularly important for the obese surgical patient. This review discusses the application of regional anesthetic techniques in obesity. Further clinical studies are needed to fill the knowledge gap about regional anesthesia and outcome in obese and morbidly obese patients.

Abstract

The prevalence of obesity is increasing worldwide. For severely obese patients, bariatric surgery is the only effective option for sustained weight loss and associated health improvement. As a consequence, the number of bariatric surgical procedures being performed is growing exponentially. Systematic knowledge regarding the effect of obesity on the pharmacokinetics and pharmacodynamics of anesthetic agents is generally lacking, and data for morbidly obese (body mass index [BMI] 40-49 kg/m2)) and super-obese patients (BMI > 50 kg/m2) are almost completely non-existent. Most drug-dosing guidelines are based on results from relatively small studies in moderately obese patients. Future systematic pharmacological research is needed for improved and more rational peri-operative care of morbidly obese patients.

Abstract

Crystalloid haemodilution has been widely found to enhance coagulation onset, but the duration of this effect has never been documented.Twelve healthy, consenting volunteers had a rapid infusion of 14 mL kg-1 of normal (0.9%) saline. Blood samples were taken, prior to (control), and immediately after (30 min) the rapid saline infusion was completed (30 min). They were then repeated at regular intervals up to 120 min. Haematocrit/platelet counts were taken to determine the degree of dilution and thrombelastograms, with and without platelet antagonists (ReoPro, Abciximab), were measured in all samples. Antithrombin levels were selectively measured.The haematocrit and platelet count showed a rapid dilutional decrease at 30 min (mean of -12.2% and -14.4%, respectively), with values returning towards baseline within 15 min after finishing the infusion. There was a significantly faster onset of coagulation (decrease in r-time) in the post-infusion sample (30 min) compared to control (P<0.05), again returning towards normal as the dilution effect was reversed. Similar thrombelastograms findings were evident in the plasma factor only group (platelets inhibited by ReoPro). Antithrombin levels changed in keeping with the haemodilution effect (P<0.0001). There was a linear relationship between antithrombin and thrombelastograms r-time (P=0.012).The faster onset of coagulation brought on by haemodilution return towards normal as the dilutional effect is reversed. This effect is mediated through plasma clotting factors. Of interest is the significant inverse correlation of the onset of coagulation increasing as the antithrombin levels decreased with dilution.

Abstract

Laparoscopic Roux-en-Y gastric bypass (RYGBP) is a commonly performed operation for morbid obesity. A significant number of patients experience postoperative nausea and vomiting (PONV) following this procedure. The aim of this study was to determine the effect, if any, of intra-operative fluid replacement on PONV.Patients who underwent laparoscopic (RYGBP) for morbid obesity during a 12-month period were included in this retrospective analysis. Demographic data including age, gender, and body mass index (BMI) were collected. Perioperative data also included total volume of intra-operative fluids administered, rate of administration, urine output, length of surgery, and incidence of PONV as determined by nursing or anesthesia records in the postanesthesia care unit (PACU). Data were analyzed by t-test.The table below depicts demographic and perioperative data, comparing patients who experienced PONV (n=125) in the PACU with those who did not (n=55). Values are mean +/- standard deviation.PONV is a common complication after laparoscopic RYGB. Patient who did not experience PONV received a larger volume of intravenous fluid at a faster rate than similar patients who complained of PONV.

Abstract

We sought to assess the effects of cardiopulmonary bypass and profound hypothermic circulatory arrest on plasma cefazolin levels administered for antimicrobial prophylaxis in cardiovascular surgery.Four groups (10 patients per group) were prospectively studied: vascular surgery without cardiopulmonary bypass (group A), cardiac surgery with a cardiopulmonary bypass time of less than 120 minutes (group B), cardiac surgery with a cardiopulmonary bypass time of greater than 120 minutes (group C), and cardiac surgery with cardiopulmonary bypass and profound hypothermic circulatory arrest (group D). Subjects received cefazolin at induction and a second dose before wound closure. Arterial blood samples were obtained preceding cefazolin administration, at skin incision, hourly during the operation, and before redosing. Cefazolin plasma concentrations were determined by using a radial diffusion assay, with Staphylococcus aureus as the indicator microorganism. Cefazolin plasma concentrations were considered noninhibitory at 8 microg/mL or less, intermediate at 16 mug/mL, and inhibitory at 32 microg/mL or greater.In group A cefazolin plasma concentrations remained greater than 16 microg/mL during the complete surgical procedure. In group B cefazolin plasma concentrations diminished to 16 microg/mL or less in 30% of the patients but remained greater than 8 microg/mL. In group C cefazolin plasma concentrations decreased to less than 16 microg/mL in 60% of patients and were less than 8 microg/mL in 50% of patients. In group D cefazolin plasma concentrations reached 16 microg/mL in 66% of the patients but decreased to 8 microg/mL in only 1 patient.For patients undergoing cardiac surgery with a cardiopulmonary bypass time of greater than 120 minutes, a single dose of cefazolin before skin incision with redosing at wound closure does not provide targeted antimicrobial cefazolin plasma levels during the entire surgical procedure. Patients undergoing profound hypothermic circulatory arrest are better protected, but the described protocol of prophylaxis is not optimal.

Abstract

Preoperative assessment of blood volume (BV) is important for patients undergoing surgery. The mean value for indexed blood volume ((In)BV) in normal weight adults is 70 mL/kg. Since (In)BV decreases in a non-linear manner with increasing weight, this value cannot be used for obese and morbidly obese patients. We present an equation that allows estimation of (In)BV over the entire range of body weights.

The role of the craniospinal nerves in mediating the antinociceptive effect of transcranial electrostimulation in the ratANESTHESIA AND ANALGESIANekhendzy, V., Davies, M. F., Lemmens, H. J., Maze, M.2006; 102 (6): 1775-1780

Abstract

Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, but its mechanism of action has not been elucidated. In a recently introduced clinically relevant rat model of TES we have validated and characterized the TES antinociceptive effect, suggesting involvement of the sensory nerves of the rat's scalp in mediating that effect. In this study, we have further investigated the role of the craniospinal nerves by attempting to block the TES antinociceptive effect with local anesthetic injected under the TES electrodes. We also applied different transcutaneous electrical nerve stimulation modalities through the TES electrodes and compared the elicited antinociceptive effect to that of TES. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick latency test in awake, unrestrained male rats. Data were analyzed by one-way analysis of variance followed by the Bonferroni t-test. The TES antinociceptive effect was significantly reduced after local anesthetic injection, and administration of 100 Hz transcutaneous electrical nerve stimulation was, over time, capable of eliciting the same degree of antinociceptive effect as TES. We conclude that sensory craniospinal nerves play a critical role in mediating the TES antinociceptive action and offer a hypothesis on the underlying mechanism(s) responsible for this action.

Abstract

Enrichment strategies which select subjects who appear to respond to the drug have been used in drug studies to demonstrate clinical efficacy. We have used clinical trial simulation techniques to examine factors that are relevant in clinical trial design based on enrichment where poor responders are excluded from the double-blind phase of the study.Simulations were performed for an analgesic trial design involving an open-dose titration phase (enrichment phase) followed by a double-blind, randomized, placebo-controlled maintenance phase. Enrichment was examined by excluding subjects above a predefined pain score (cutoff) from analysis of efficacy for the maintenance phase. Cutoff pain scores ranging from 4 to 7 on a 0 to 10 categorical scale were examined. A database consisting of chronic pain patients who participated in studies with a new formulation of buprenorphine was used to build the simulation model. Since no data were available for the key model variable "correlation between treatment and placebo response", values of 0.25, 0.5, and 0.75 were used for the simulations.A correlation between treatment and placebo effect ranging from 0.75 to 0.25 will cause the likelihood of trial success to vary from 50% to 95%. This model also shows that recruitment efficiency will decrease with the use of lower cutoff pain scores.Prior to using enrichment techniques, investigators must consider the correlation between treatment effect and placebo response to optimize clinical trial design.

Abstract

This study was designed to examine whether a handheld, battery-operated fiberoptic bronchoscope (FOB) used to verify endotracheal tube (ETT) placement would be as sensitive and specific as other modes and whether a combination of multiple modes would further enhance the sensitivity and specificity of ETT placement verification.An academic hospital-based air medical program.This was a prospective, randomized study examining surgical patients undergoing general endotracheal anesthesia. Eighteen critical care transport (CCT) nurses, previously unfamiliar with FOB, were asked to identify intratracheal and intraesophageal ETTs by using misting, end-tidal carbon dioxide concentration (ETCO(2)), and FOB alone or with a combination of all three modes. The sensitivity and specificity of single and multimode verification were calculated and compared.Comparison of ETT verification by single mode alone revealed a rank order of sensitivity with ETCO(2) (0.97) > FOB (0.87) > misting (0.84), whereas all three modes had similar specificities (0.93-0.94). However, the use of the three-mode combination revealed a sensitivity and specificity of 1.0.As a single mode for ETT verification, use of a handheld, battery-operated FOB device allowed for direct visualization and had an 87% sensitivity and 93% specificity. When combined with misting and ETCO(2), FOB allowed 100% successful verification of ETT placement.

Abstract

The second gas effect (SGE) is considered to be significant only during periods of large volume N(2)O uptake (VN(2)O); however, the SGE of small VN(2)O has not been studied. We hypothesized that the SGE of N(2)O on sevoflurane would become less pronounced when sevoflurane administration is started 60 min after the start of N(2)O administration when VN(2)O has decreased to approximately 125 ml min(-1), and that the kinetics of sevoflurane under these circumstances would become indistinguishable from those when sevoflurane is administered in O(2).Seventy-two physical status ASA I-II patients were randomly assigned to one of six groups (n=12 each). In the first four groups, sevoflurane (1.8% vaporizer setting) administration was started 0, 2, 5 and 60 min after starting 2 litre min(-1) O(2) and 4 litre min(-1) N(2)O, respectively. In the last two groups, sevoflurane (1.8 or 3.6% vaporizer setting) was administered in 6 litre min(-1) O(2). The ratios of the alveolar fraction of sevoflurane (Fa) over the inspired fraction (Fi), or Fa/Fi, were compared between the groups.Sevoflurane Fa/Fi was larger in the N(2)O groups than in the O(2) groups, and it was identical in all four N(2)O groups.We confirmed the existence of a SGE of N(2)O. Surprisingly, when using an Fa of 65% N(2)O, the magnitude of the SGE was the same with large or small VN(2)O. The classical model and the graphical representation of the SGE alone should not be used to explain the magnitude of the SGE. We speculate that changes in ventilation/perfusion inhomogeneity in the lungs during general anaesthesia result in a SGE at levels of VN(2)O previously considered by most to be too small to exert a SGE.

Abstract

The appropriate dose of succinylcholine (SCH) in morbidly obese patients is unknown. We studied 45 morbidly obese (body mass index >40 kg/m2) adults scheduled for gastric bypass surgery. The response to ulnar nerve stimulation of the adductor pollicis muscle at the wrist was recorded using the TOF-Watch SX acceleromyograph. In a randomized double-blind fashion, patients were assigned to one of three study groups. In Group I, patients received SCH 1 mg/kg ideal body weight, in Group II 1 mg/kg lean body weight, and in Group III 1 mg/kg total body weight. After SCH administration, endotracheal intubating conditions were scored. The recovery from neuromuscular block was recorded for 20 min. There was no difference in the onset time of maximum neuromuscular blockade among groups, but maximum block was significantly less in Group I. The recovery intervals were significantly shorter in Groups I and II. In one third of the patients in Group I, intubating conditions were rated poor, whereas no patient in Group III had poor intubating conditions. Our study demonstrates that for complete neuromuscular paralysis and predictable laryngoscopy conditions, SCH 1 mg/kg total body weight is recommended.

Abstract

Kinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (FA) generated by the physiological uptake and distribution models used by the Gas Man program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows.Gas Man was used to generate FA vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L x min(-1)), a constant alveolar minute ventilation (4 L x min(-1)), and a constant inspired concentration (FI) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these FI, simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L x min(-1)) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L x min(-1)). Two and three compartmental models were fitted to FA of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L x min(-1) for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an FI of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%.A three-compartment model fitted the data best (MDPE = 0% and MDAPE < or = 0.074%) and performed equally well when tested prospectively (MDPE < or = 0.51% and MDAPE < or = 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex.The kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively.

Abstract

A simple formula for estimating ideal body weight (IBW) in kilograms for both men and women is presented. The equation IBW = 22 x H2, where H is equal to patient height in meters, yields weight values midway within the range of weights obtained using published IBW formulae.

Abstract

The study's goal was to determine if cardiac output (CO), obtained by impedance cardiography (ICG), would be improved by a new equation N, implementing a square root transformation for dZ/dtmax/Z0, and a variable magnitude, mass-based volume conductor Vc. Pulmonary artery catheterisation was performed on 106 cardiac surgery patients pre-operatively. Post-operatively, thermodilution cardiac output (TDCO) was simultaneously compared with ICG CO. dZ/dtmax/Z0 and Z0 were obtained from a proprietary bioimpedance device. The impedance variables, in addition to left ventricular ejection time TLVE and patient height and weight, were input using four stroke volume (SV) equations: Kubicek (K), Sramek (S), Sramek-Bernstein (SB), and a new equation N. CO was calculated as SV x heart rate. Data are presented as mean +/- SD. One way repeated measures of ANOVA followed by the Tukey test were used for inter-group comparisons. Bland-Altman methods were used to assess bias, precision and limits of agreement. P< 0.05 was considered statistically significant. CO implementing N (6.06 +/- 1.48 l min(-1)) was not different from TDCO (5.97 +/- 1.41 l min(-1)). By contrast, CO calculated using K (3.70 +/- 1.53 l min(-1)), S (4.16 +/- 1.83 l min(-1)) and SB (4.37 +/- 1.82 l min(-1)) was significantly less than TDCO. Bland-Altman analysis showed poor agreement between TDCO and K, S and SB, but not between TDCO and N. Compared with TDCO, equation N, using a square-root transformation for dZ/dtmax/Z0, and a mass-based Vc, was superior to existing transthoracic impedance techniques for SV and CO determination.

Abstract

To determine which patient parameters best predict left bronchial width (LBW) when selecting the correct size double-lumen tube (DLT). If LBW is known, a DLT that will fit that bronchus can be chosen.Prospective study.University medical center.Three hundred twenty-one consecutive patients scheduled for thoracic surgery and for whom there was a chest radiograph and for whom tracheal width (TW) and LBW could be measured.Tracheal width and LBW were directly measured from the chest radiograph. Patient demographic data were recorded and then analyzed to see which factor(s) best predicted LBW. Parameters often used for DLT selection (age, sex, height, and weight) as well as TW were compared by univariate and multivariate statistical analysis to see which factor(s) most accurately predicted LBW.There were weak but significant correlations between age and height and LBW in men, and height and LBW in women. Multivariate statistical analysis showed that, for both men and women, TW was the best predictor of LBW. Sex, height, and weight did not improve predictability over TW alone. The equation that best predicts LBW for both sexes is: LBWmm = (0.50)(TWmm) + 3.7 mm. This model explains 46% of the variance in LBW. As structures measured from a chest radiograph are magnified by 10%, the formula to predict LBW, which normalizes for this magnification factor, is: LBWmm = (0.45)(TWmm(CXR)) + 3.3 mm.Direct airway measurement is the most accurate way to select an appropriate DLT. However, when direct measurement of LBW cannot be performed, estimating LBW from TW is a better predictor of LBW than either sex, height, or weight.

Abstract

To assess intubating conditions without neuromuscular blocking drugs, to determine the relation between the dose of rocuronium and the probability of achieving excellent or at least good (good or excellent) intubating conditions with the intubating laryngeal mask airway (ILMA), and finally, to determine the relationship between rocuronium use and the success rate of endotracheal intubation.Prospective, randomized, double-blinded, placebo-controlled study.University-affiliated medical center.Sixty American Society of Anesthesiologists physical status I and II patients undergoing elective surgery.Anesthesia was induced with propofol 2.5 mg/kg and fentanyl 1 microg/kg. One minute after loss of consciousness, patients received rocuronium 0.2 mg/kg or saline. In the rocuronium group, if intubating conditions were scored as poor, rocuronium dose in the next patient was increased by 0.05 mg/kg. If intubating conditions were scored as good, no change was made, but if conditions were scored as excellent, the dose was decreased by 0.05 mg/kg. One minute after rocuronium or saline administration, an ILMA was used to intubate the trachea. If intubation was unsuccessful, a second attempt was made using the ILMA.We recorded intubating conditions and the success rate of tracheal intubation.Without rocuronium, the probability of achieving at least good intubating conditions with the ILMA was 30%. A rocuronium dose of 0.2 mg/kg resulted in a probability of 80% to achieve at least good intubating conditions. Rocuronium significantly increased the success rate of the second intubation attempt.To achieve good or excellent intubating conditions with the ILMA, a rocuronium dose lower than the standard intubating dose of 0.6 mg/kg can be used. Neuromuscular blockade increases the success rate of intubation if a second attempt is necessary.

Abstract

Nitrous oxide (N2O) is frequently used to supplement more potent anesthetic agents. One side-effect of N2O is its ability to expand an air-containing space. We investigated if N2O adversely affected operating conditions by distending normal bowel during laparoscopic bariatric procedures.50 morbidly obese patients were divided into 2 study groups. Group 1 patients were ventilated with a halogenated anesthetic/oxygen/air mixture, while Group 2 received a halogenated anesthetic/oxygen/N2O mixture. At 30, 60, and 90 min intervals during the operation, the surgeon was asked if N2O was being used.The surgeons responded correctly only 42% (30 min), 50% (60 min), and 48% (90 min) of the time. In Group 2 (N2O) patients, they incorrectly answered that N2O was not being used 88% (30 min), 68% (60 min), and 68% (90 min); and in Group 1 (air) patients, they incorrectly answered that N2O was being used 28% (30 min), 32% (60 min), and 36% (90 min) of the time.We found that using N2O did not cause noticeable bowel distention during laparoscopic bariatric procedures of relatively short duration.

Abstract

Surgery for intracranial aneurysm often results in postoperative neurologic deficits. We conducted a randomized trial at 30 centers to determine whether intraoperative cooling during open craniotomy would improve the outcome among patients with acute aneurysmal subarachnoid hemorrhage.A total of 1001 patients with a preoperative World Federation of Neurological Surgeons score of I, II, or III ("good-grade patients"), who had had a subarachnoid hemorrhage no more than 14 days before planned surgical aneurysm clipping, were randomly assigned to intraoperative hypothermia (target temperature, 33 degrees C, with the use of surface cooling techniques) or normothermia (target temperature, 36.5 degrees C). Patients were followed closely postoperatively and examined approximately 90 days after surgery, at which time a Glasgow Outcome Score was assigned.There were no significant differences between the group assigned to intraoperative hypothermia and the group assigned to normothermia in the duration of stay in the intensive care unit, the total length of hospitalization, the rates of death at follow-up (6 percent in both groups), or the destination at discharge (home or another hospital, among surviving patients). At the final follow-up, 329 of 499 patients in the hypothermia group had a Glasgow Outcome Score of 1 (good outcome), as compared with 314 of 501 patients in the normothermia group (66 percent vs. 63 percent; odds ratio, 1.14; 95 percent confidence interval, 0.88 to 1.48; P=0.32). Postoperative bacteremia was more common in the hypothermia group than in the normothermia group (5 percent vs. 3 percent, P=0.05).Intraoperative hypothermia did not improve the neurologic outcome after craniotomy among good-grade patients with aneurysmal subarachnoid hemorrhage.

Abstract

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. After receiving a transplant, survival rates are higher and comorbidities may resolve. As a consequence, more patients with significant comorbidities such as advanced cardiovascular disease will present for transplantation. This review highlights commonly encountered issues in patients undergoing kidney transplantation and recommendations are made for their anesthetic management.

Abstract

The effect of patient position on the view obtained during laryngoscopy was investigated.60 morbidly obese patients undergoing elective bariatric were studied. Patients were randomly assigned into one of two groups. In Group 1, a conventional "sniff" position was obtained by placing a firm 7-cm cushion underneath the patient's head, thus raising the occiput a standard distance from the operating-table while the patient remained supine. In Group 2, a "ramped" position was achieved by arranging blankets underneath the patient's upper body and head until horizontal alignment was achieved between the external auditory meatus and the sternal notch. Following induction of general anesthesia, tracheal intubation was performed using a Video MacIntosh laryngoscope. The laryngoscopy and intubation sequences were recorded onto videotape. Three independent investigators, unaware as to which position the patient had been in at the time of tracheal intubation, then viewed the videotape and assigned a numerical grade to the best laryngeal view obtained.The "ramped" position improved the laryngeal view when compared to a standard "sniff" position, and this difference was statistically significant (P=0.037).The "ramped" position is superior to the standard "sniff" position for direct laryngoscopy in morbidly obese patients.

Abstract

Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, allowing a substantial reduction of intraoperative opioids. Acceptance of TES into clinical practice is hampered by lack of controlled clinical trials and inconclusive animal data regarding the TES antinociceptive action. This inconclusive data may be explained, in part, by failure in rat experiments to simulate the variables used in humans when TES electrodes are positioned on the skin. In this study we validated the TES antinociceptive effect in a novel animal model of cutaneously administered TES, when the stimulating conditions mimic the ones used in clinical practice. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick and hot-plate latency tests in awake, unrestrained male rats. Data were analyzed by analysis of variance and mixed-effects population modeling. The administration of TES at 2.25 mA produced an almost immediate, sustained, frequency-dependent (40-60 Hz) antinociceptive effect, reaching approximately 50% of the maximal possible value. We conclude that an antinociceptive effect of cutaneously administered TES can be demonstrated in the rat. Some characteristics of the effect suggest an important role of the sensory nerves of the rat's scalp in mediating the TES antinociceptive response.Transcranial electrostimulation produces a significant, frequency-dependent antinociceptive effect that may be mediated by cutaneous nerves of the scalp.

Heat and moisture exchange devices: Are they doing what they are supposed to do?ANESTHESIA AND ANALGESIALemmens, H. J., Brock-Utne, J. G.2004; 98 (2): 382-385

Abstract

Heat and moisture exchangers (HMEs) are used to provide humidification and warming of the inspiratory gases during general anesthesia. The performance specifications provided by manufacturers of HMEs are based on in vitro measurements of moisture output using the International Standards Organization (ISO) 9360 method. We studied the in vivo performance of three different HMEs with similar ISO specifications in a randomized crossover fashion in patients under general anesthesia. The effect of each HME on temperature, convective heat loss, evaporative heat loss, total heat loss, relative humidity, and absolute humidity of inspiratory gases was determined. Although all HMEs in general improved baseline variables, we found significant differences in performance for the different HMEs. In only one type did the moisture output correspond with ISO specifications. We conclude that the in vivo performance of HMEs may not correspond with manufacturer's specifications.There is considerable variability in the in vivo performance of heat and moisture exchangers that have similar manufacturer specifications. These specifications, based on the International Standards Organization 9360 standard, which is measured in vitro, cannot be used to predict clinical performance.

Abstract

To determine the association between bispectral index (BIS) and seizure duration obtained by electroconvulsive therapy (ECT) administered sooner or later after anesthetic induction.Prospective, randomized, crossover study.University-affiliated medical center.Nine ASA physical status I, II, and III patients undergoing a total of 31 ECTs.ECT was administered soon (<210 sec) or later (between 210 sec and 360 sec) after anesthetic induction. In each individual patient, drug regimens and ECT machine settings were identical.BIS immediately before the start of the ECT and the duration of the EEG seizure were recorded, as well as the time period between loss of consciousness and ECT administration.There was no relationship between BIS level and seizure duration. Moreover, seizure duration was not dependent on the time of ECT administration in the time window between one and 6 minutes after loss of consciousness.The hypnotic drug effect measured by the BIS is not correlated to the seizure duration obtained by ECT.

Abstract

The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide-narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia.Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol-alfentanil-nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery.No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 microg x kg(-1) x min(-1); P < 0.01) and historic control group (18.2 microg x kg(-1) x min(-1); P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3-3.8 min; P < 0.001) and standard practice control (1.4-1.5 min; P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found.Patient State Index-directed titration of propofol delivery resulted in faster emergence and recovery from propofol-alfentanil-nitrous oxide anesthesia, with modest decrease in the amount of propofol delivered, without increasing the number of unwanted events.

Abstract

The tracheas of obese patients may be more difficult to intubate than those of normal-weight patients. We studied 100 morbidly obese patients (body mass index >40 kg/m(2)) to identify which factors complicate direct laryngoscopy and tracheal intubation. Preoperative measurements (height, weight, neck circumference, width of mouth opening, sternomental distance, and thyromental distance) and Mallampati score were recorded. The view during direct laryngoscopy was graded, and the number of attempts at tracheal intubation was recorded. Neither absolute obesity nor body mass index was associated with intubation difficulties. Large neck circumference and high Mallampati score were the only predictors of potential intubation problems. Because in all but one patient the trachea was intubated successfully by direct laryngoscopy, the neck circumference that requires an intervention such as fiberoptic bronchoscopy to establish an airway remains unknown. We conclude that obesity alone is not predictive of tracheal intubation difficulties.In 100 morbidly obese patients, neither obesity nor body mass index predicted problems with tracheal intubation. However, a high Mallampati score (greater-than-or-equal to 3) and large neck circumference may increase the potential for difficult laryngoscopy and intubation.

Abstract

This study compared the pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic (PK/PD) profile of zaleplon, a new pyrazolopyrimidine hypnotic, with those of zolpidem and placebo.This was a double-blind, 5-period crossover study in which healthy volunteers with no history of sleeping disorder were randomized to 10- or 20-mg oral doses of zaleplon, 10- or 20-mg oral doses of zolpidem, or placebo. The pharmacokinetic characteristics of the active drugs were estimated using a noncompartmental method and NONMEM. Pharmacodynamic characteristics were determined using psychophysical tests, including measures of sedation, mood, mental and motor speed, and recent and remote recall. Results of these tests were used to compare the drugs' relative PK/PD profiles.Ten healthy male and female volunteers, aged 23 to 31 years, took part in the study. The apparent elimination half-life of zaleplon (60.1+/-8.9 min) was significantly shorter than that of zolpidem (124.5+/-37.9 min) (P < 0.001). Zaleplon produced less sedation than zolpidem at the 2 doses studied (P < 0.001). The sedation scores of the zaleplon groups returned to baseline in less time than those of the zolpidem groups (4 vs 8 hours; P < 0.05). Zaleplon had no effect on recent or remote recall, whereas zolpidem had a significant effect on both measures (P < 0.05).In this study in 10 young, healthy volunteers, zaleplon was eliminated more rapidly, produced no memory loss, and caused less sedation than zolpidem at the same doses.

Abstract

Certain vital dyes are known to cause pulse oximetry (Spo2) desaturation. The authors studied the effect of isosulfan blue (IB) on Spo2.Thirty-three women, aged 34-81 yr, who were undergoing surgery for breast cancer were studied. IB, 5 ml (50 mg), was injected intraparenchymally around the tumor area by the surgeon. A pulse oximeter was used to continuously record Spo2 values up to 130 min after IB injection. Friedman repeated-measures analysis of ranks was used to analyze the baseline Spo2 and values at 5, 10, 20, 30, 40, 50, and 60 min.Spo2 values were significantly different from baseline values at 5, 10, 20, 30, 40, 50, and 60 min (P < 0.05). In a typical patient, a maximum Spo2 decrease of 3% can be anticipated 25 min after injection of IB.After peritumoral administration of IB, 50 mg, a significant interference with Spo2 will occur.

Abstract

We examined the effect of four maintenance anaesthetics on the neuromuscular blocking activity and spontaneous recovery characteristics after a short-term infusion of rapacuronium. Eighty ASA I-III adult patients undergoing elective surgery were studied at four centres. Anaesthesia was induced with propofol 1.5-2.5 mg kg-1 and fentanyl 1-2 micrograms kg-1, followed by a bolus of rapacuronium 1.5 mg kg-1. The patients were randomized to receive either desflurane (2-4% end-tidal, ET), sevoflurane (0.75-1.5% ET), isoflurane (0.4-0.8% ET), or a propofol infusion (75-150 micrograms kg-1 min-1) for maintenance of anaesthesia in combination with nitrous oxide (60-70%) in oxygen. When the first twitch (T1) of a train-of-four stimulus (using the TOF Guard accelerometer) returned to 5%, an infusion of rapacuronium was started at 3 mg kg-1 h-1 and adjusted to maintain T1/T0 at 10%. The duration of infusion lasted between 45 and 60 min, and the average infusion rates of rapacuronium were similar in all groups, ranging from 1.6 to 2.5 mg kg-1 h-1. There were no significant differences among the groups in the times for T1/T0 to return to 25%, 75% or 90%, or for T4/T1 to return to 70% and 80% upon discontinuation of the infusion. When potent inhalation anaesthetics are used in clinically relevant concentrations for maintenance of anaesthesia, the neuromuscular recovery profile of rapacuronium administered as a variable-rate infusion for up to 1 h is similar to that found with a propofol-based anaesthetic technique.

Abstract

Remifentanil blood concentrations necessary for adequate intraoperative anesthesia have not been defined. The goal of this study was to determine the blood concentrations of remifentanil needed for anesthesia with 66% nitrous oxide during intraabdominal surgery. In addition, the pharmacokinetics of remifentanil and the effects of covariates on both the pharmacodynamics and the pharmacokinetics were determined.Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and remifentanil. Remifentanil was administered by a computer-controlled infusion pump that rapidly attained, and then maintained, constant remifentanil blood concentrations. If the patient showed signs of inadequate anesthesia (autonomic or somatic response), the target concentration was increased by 1 or 2 ng/ml. If no response occurred during a 15-min period, the concentration was decreased by 1 or 2 ng/ml. Remifentanil pharmacodynamics and pharmacokinetics were estimated using NONMEM.The remifentanil blood concentration for which there is a 50% probability of adequate anesthesia during abdominal surgery (Cb50) with 66% nitrous oxide was 4.1 ng/ml in men and 7.5 ng/ml in women. The Cb50 values for prostatectomy, nephrectomy, and other abdominal procedures were 3.8, 5.6, and 7.5 ng/ml, respectively. Remifentanil pharmacokinetics were best described by a two-compartment model with lean body mass as a significant covariate, where V1 = 0.129(lean body mass-50) + 3.79 l, V2 = 6.87 l, CL1 = 0.0389(lean body mass-50) + 2.34 l/min and CL2 = 1.14 l/min.The Cb50 differed according to patient gender. However, because surgery type was not specified for each man or woman, this may reflect a difference in surgical procedure.

Abstract

An intravenous loading dose is given to rapidly achieve a desired drug concentration in the blood. A loading dose calculated with the volume of distribution (Vd) at steady state will result in high peak concentrations and possibly serious adverse effects. A loading dose based on the central compartment Vd (Vc) followed by a maintenance infusion may also miss the target drug concentration and cause serious adverse effects. The Vd can be viewed as a time-dependent variable that expands from the Vc immediately after injection, to eventually include the steady-state Vd. If the loading dose is calculated from a Vd determined after the time of peak effect (tmax), then the actual concentration will exceed the target concentration at the tmax. If a loading dose is calculated from a Vd before the peak effect occurs, the actual concentration will be insufficient to achieve the target concentration at tmax. A loading dose based on the Vd at the tmax will accurately achieve the concentration at the tmax without unexpected adverse effects. To determine the Vd at peak effect, it is necessary that an effect can be measured, the peak effect can be detected and the plasma concentrations are sampled frequently enough to quantify the plasma concentrations at the tmax. For drugs that attain an ultra-fast effect (1 to 2 minutes), arterial samples need to be measured. If the onset of effect is intermediate or slow, venous blood can be sampled as the arterial and venous concentrations may be similar at the tmax.

Abstract

Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil.Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y.The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively.This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.

Abstract

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.

Abstract

The pure mu-receptor opioid agonists fentanyl, sufentanil and alfentanil are commonly used to provide the specific anti-nociceptive component of a balanced anaesthesia technique. Trefentanil and remifentanil are new opioids with a very short duration of action. Remifentanil has an ester structure and is very rapidly metabolised by blood and tissue esterases. Different perioperative stimuli require different plasma concentrations to suppress responses of the patient. The ability of the anaesthesiologist to select a precise dosage scheme for the individual patient is impeded by the large interindividual pharmacokinetic and pharmacodynamic variability. In addition, the combination of opioids and other drugs used to produce the desired components of balanced anaesthesia may exert additive, synergistic or antagonistic effects. Knowledge of factors influencing the pharmacokinetics and pharmacodynamics is still fragmentary and often controversial. Consequently, the opioid dose needs to be adjusted according to the responses of the patient during surgery to ensure adequate anaesthesia and rapid recovery. The duration of action is not predicted by the elimination half-life alone. The decline in effect-site concentration is dependent on the complex entity of infusion duration, and pharmacokinetic and pharmacodynamic parameters. Computer simulations of infusions of varying duration have been extremely useful when selecting an opioid for a specific clinical scenario on a rational basis. Traditionally, opioids are still administered by intermittent bolus injections. A disadvantage of this method of administration is that plasma concentrations fluctuate above and below the level required for adequate anaesthesia. Computer-assisted infusion pumps make it possible to target a particular drug concentration in plasma and to maintain or change this concentration as needed. This technique provides more stable anaesthesia and a more rapid recovery of the patient.

Abstract

The safety, pharmacokinetics, and pharmacodynamics of the investigational partial opioid agonist, mirfentanil, were determined in a dose-escalating, Phase 1 study in healthy male volunteers. Hemodynamic, central nervous system, and respiratory monitoring were used for safety assessment. The electroencephalogram (EEG) was evaluated as a surrogate measure of drug effect. Butorphanol was chosen as the control drug. In the mirfentanil group (n = 8) the dose was increased in sequential subjects from 25 micrograms.kg-1.min-1 for 30 min to 450 micrograms.kg-1.min-1 for 15 min, and in the butorphanol group (n = 10) from 2 micrograms.kg-1.min-1 for 30 min to 25 micrograms.kg-1.min-1 for 15 min. In the mirfentanil group, serious side effects were observed at plasma concentrations more than 2000 ng/mL: heart rates exceeded 130 bpm (n = 2), epileptiform EEG potentials (n = 2), and a convulsion (n = 1). The clearance of mirfentanil was high (5.8-7.2 L/min), and the volume of distribution large (247-348 L). The EEG of the subjects receiving mirfentanil showed no changes typical for opioids. Butorphanol however, caused intermittent slowing in the delta and theta ranges. The results of our study define the upper limit of safe plasma concentrations in future mirfentanil studies.

Abstract

We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical dosing scenarios.First, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes.The pharmacokinetic-pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were as follows: Elimination clearance, 0.444 +/- 0.073 versus 0.184 +/- 0.031 L/min; steady-state distribution volume, 37 +/- 7 versus 23 +/- 3 L; and elimination half-life, 127 +/- 24 versus 114 +/- 19 minutes. Trefentanil versus alfentanil pharmacodynamics were as follows: the equilibration half-time between EEG effect and arterial drug concentration, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng/ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable-length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl.We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.

Abstract

Remifentanil (GI87084B) is a new short-acting opioid with a unique ester structure. Metabolism of remifentanil by ester hydrolysis results in very rapid elimination. The aim of this study was to characterize in detail the pharmacokinetic profile of remifentanil in healthy male volunteers.Ten healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 micrograms.kg-1.min-1 for 20 min. Frequent arterial blood samples were drawn and analyzed by gas chromatographic mass spectroscopy to determine the remifentanil blood concentrations. The raw pharmacokinetic data were analyzed using three different parametric compartmental modeling methods (traditional two-stage, naive pooled data, and NONMEM). The raw pharmacokinetic data also were analyzed using numeric deconvolution and a nonparametric moment technique. A computer simulation using hte pharmacokinetic parameters of the NONMEM compartmental model was performed to provide a more intuitively meaningful and clinically relevant description of the pharmacokinetics. The simulation estimated the time necessary to achieve a 50% decrease in remifentanil concentration after a variable-length infusion.For each parametric method, a three-compartment mamillary model that accurately describes remifentanil's concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 l/min, a volume of distribution at steady state of 32.8 l, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 l/min, a volume of distribution at steady state of 31.8 l, and a mean residence time of 10.9 min. The computer simulation revealed the strikingly unique pharmacokinetic profile of remifentanil compared to that of the currently available fentanyl family of opioids.Remifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.

Abstract

Although computer-controlled infusion (CCI) of alfentanil has been shown to be effective intraoperatively, this technique has not been validated for postoperative use. Therefore, the authors examined the efficacy of this technique in providing postoperative pain relief. The study comprised both a validation of published pharmacokinetic data sets and the definition of the minimum effective analgesic concentrations after major orthopedic surgery.The bias and inaccuracy of the implemented pharmacokinetic data set were examined, in 20 patients who had undergone major orthopedic surgery, by determination of the median performance error (MDPE) and median absolute performance error (MDAPE). The performance of two other published pharmacokinetic data sets was also examined by simulating the plasma concentrations that would have been predicted, had these data sets been implemented. The minimum effective analgesic concentrations (MEAC) were determined at the following time points: at the onset of pain, at 9:00 PM on the day of surgery, and at 9:00 AM and 9:00 PM on the first postoperative day.Measured plasma concentration-time profiles generally were parallel to the target concentration-time profiles. The MDPE and MDAPE obtained were 12% and 28%, respectively. The MEACs ranged from < 1 to 175 ng/ml and showed substantial interindividual variability. The median MEACs at the four study times were 59, 52, 65, and 43 ng/ml. The MEAC at 9:00 PM on the first postoperative day was significantly lower than those at the other study times (P < 0.05).Computer-controlled infusion of alfentanil provides adequate postoperative analgesia. The study demonstrated that pharmacokinetic data sets that are useful for intraoperative CCI of alfentanil are equally valid in the postoperative phase. Although required plasma concentrations of alfentanil are reasonably stable in time, interindividual variations are large, necessitating individual titration.

Abstract

Although the clinical properties of propofol have been studied extensively, the pharmacodynamics have not yet been described fully. We studied the propofol concentration-effect relationships for loss of eyelash reflex, loss of consciousness, and hemodynamic changes in 18 female patients, ASA physical status 1, aged 20-49 yr. Propofol was given by computer-controlled infusion. The initial target concentration of 0.5-1 microgram/ml was increased every 12 min by 0.5-1 microgram/ml until the patients lost consciousness. Every 3 min, loss of eyelash reflex and loss of consciousness were tested and an arterial blood sample was taken for analysis of the blood propofol concentration. The concentration-response relationships for loss of eyelash reflex and loss of consciousness were defined by fitting a sigmoid Emax function (where Emax = the maximum effect that can be reached; i.e., 100% of the patients showing loss of eyelash reflex or loss of consciousness) to the response/no response data versus the propofol concentration, using nonlinear regression. The effect of propofol on hemodynamic parameters was analyzed by linear regression. The propofol concentrations at which 50% and 90% of the patients showed loss of eyelash reflex were 2.07 and 2.78 micrograms/ml, respectively. The corresponding values for loss of consciousness were 3.40 and 4.34 micrograms/ml. The systolic and diastolic blood pressure decreased with increasing blood propofol concentration. The correlation coefficients for the decrease in systolic and diastolic blood pressure versus the blood propofol concentration were r2 = -0.663 and r2 = -0.243, but heart rate did not change. In conclusion, propofol concentrations inducing loss of eyelash reflex are less than those inducing loss of consciousness.

Abstract

The role of protein binding in relation to the pharmacodynamics of alfentanil was investigated in 15 female and 13 male patients, aged 21-85 yr, ASA physical status 1 or 2, undergoing upper abdominal surgery. All patients had normal cardiac, hepatic, renal, and pulmonary function. None was receiving medication or had a history of alcohol or other drug abuse. Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and alfentanil. Alfentanil was administered by a computer-controlled infusion pump. If, during surgery, the patient exhibited signs of inadequate anesthesia (i.e., response), the target alfentanil plasma concentration was increased by 50-100 ng/ml. If there was no response during a 15-min period, the target concentration was decreased by 50-100 ng/ml. Arterial blood samples were taken before any change of the target concentration and 4 min after the computer had indicated that the new target concentration had been reached. In addition, blood samples were taken before intubation, skin incision, and in the patients in whom ventilation recovered spontaneously before extubation. In the remaining patients a blood sample was taken before the administration of naloxone. Plasma alfentanil concentrations were determined by capillary gas chromatography. Alfentanil protein binding was determined by equilibrium dialysis in an arterial blood sample taken before induction of anesthesia. Alfentanil concentration-effect data were evaluated by logistic regression, where effect was either response or no response to perioperative stimuli. The average free fraction of alfentanil was 9.3 +/- 3.9% (range 3.7-19.1%). For intubation, skin incision, and postanesthesia ventilation, it was not possible to characterize the concentration-effect curves based on total plasma concentrations with logistic regression.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Studies on the effects of age on the pharmacokinetics of alfentanil are inconclusive. A possible factor in explaining the differences between various studies could be the effect of gender. The authors studied the effects of age on the pharmacokinetics of alfentanil in female (n = 21) and male (n = 15) patients undergoing lower abdominal surgery under nitrous oxide alfentanil anaesthesia. There was a significant negative correlation (r = -0.79, p less than 0.001) between plasma alfentanil clearance (CL) and age in women (less than 50y, median CL 24.84 L/h; greater than 50y, median CL 14.52 L/h), but not in men (less than 50y, median CL 19.44 L/h; greater than 50y, median CL 16.2 L/h). The conclusion is drawn that the effects of age on the pharmacokinetics of alfentanil are gender-dependent.

Abstract

Two groups of women, ASA physical status 1, undergoing surgery for primary breast cancer, were studied to assess the effect of alcohol intake on alfentanil pharmacodynamics. Patients in group 1 (n = 6) had an average daily consumption of 20-40 g alcohol. Patients in group 2 (n = 8) were life-long abstainers or drank only occasionally (less than 60 g per year). Anesthesia was induced and maintained with 66% N2O in O2 and alfentanil. Alfentanil was administered by a computer-controlled infusion pump. If during surgery the patient exhibited somatic, hemodynamic, or other autonomic signs of inadequate anesthesia (response), the target alfentanil plasma concentration was increased by 50-100 ng/ml. If there was no response during a 15-min period, the target concentration was decreased by 50-100 ng/ml. Arterial blood samples were taken before any change of the target concentration, 4 min after a new predicted target concentration was achieved, and at extubation. Plasma concentrations were determined by capillary gas chromatography. Alfentanil protein binding was measured by equilibrium dialysis. Plasma alfentanil concentration-effect data were analyzed by nonlinear regression, where effect was either response or no response to surgical stimuli. The average total alfentanil requirement was significantly (P less than 0.005) higher in group 1 (3.7 +/- 1.2 micrograms.kg-1.min-1) than in group 2 (1.9 +/- 0.4 micrograms.kg-1.min-1). The average Cp50 (the plasma concentration for which the probability of no response during surgery is 50%) was significantly (P less than 0.001) higher in group 1 (522 +/- 104 ng/ml) than in group 2 (208 +/- 26 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Effects of age on the pharmacodynamics of alfentanil, as a supplement to nitrous oxide anesthesia, were studied in younger (31-52 years; n = 14) and older (56-86 years; n = 14) women undergoing curative surgery for primary breast cancer. Plasma alfentanil concentration-effect curves for perioperative stimuli and for the probability of needing naloxone at the end of the operation were fitted by logistic regression. Effects of age on the plasma concentration-effect relation of alfentanil could not be demonstrated. However, the dose requirement in the older patient group was significantly lower than in the younger patient group.

Abstract

The use of a computer-assisted infusion of alfentanil, combined with 66% nitrous oxide in oxygen, for induction and maintenance of anaesthesia was evaluated in 18 elderly patients. The target alfentanil concentration for induction was varied between 300 and 475 ng/ml, to be achieved in 2 minutes. During maintenance, the alfentanil concentration was increased or decreased according to each patient's responses. Arterial blood samples were taken for measurement of alfentanil concentration. There were high incidences of muscle rigidity, bradycardia and hypotension during induction. Hypotension was dose- and concentration-dependent. Signs of light anaesthesia during maintenance were controlled rapidly by increasing the target plasma concentration. Nine patients required naloxone at the end of surgery. Ventilatory depression recurred in three of these. The use of published alfentanil pharmacokinetic data from elderly patients to predict plasma concentrations during prolonged infusion resulted in significant prediction errors, notably in the higher concentration range.

Abstract

The pharmacodynamics of alfentanil given as a supplement to nitrous oxide anaesthesia were studied in 10 elderly patients undergoing lower abdominal surgery. Plasma alfentanil concentration-effect curves for perioperative stimuli and for the probability of needing naloxone at the end of surgery were fitted by logistic regression. The concentration at which the probability of no response was 0.5 (Cp50) for laryngoscopy was 356 ng ml-1, for opening the peritoneum 295 ng ml-1 and for closing the peritoneum 254 ng ml-1. The average Cp50 for the intra-abdominal part of the operation was 268 +/- 97 ng ml-1. The Cp50 for needing naloxone was 174 ng ml-1. These findings are similar to published values for young healthy females undergoing lower abdominal surgery. Our findings suggest that the pharmacodynamics of alfentanil in the elderly are similar to those in younger adults.